Phosphonic acid and their derivatives have become increasingly important in recent years due to their useful biological properties, such as their ability to lower blood pressure due to their angiotensin converting enzyme inhibition activity, such as disclosed in U.S. Pat. No. 4,316,896 to Thorsett et al and U.S. Pat. Nos. 4,168,267 to Petrillo and 4,452,790 to Karanewsky et al.
The Arbuzov reaction of trialkylphosphites with suitable alkylating agents is a commonly used method for the preparation of phosphonic acid esters but it often requires high temperatures, neat reaction mixtures and other strong impractical conditions. Additionally, complex product mixtures are common due to competitive alkylation by alkyl halide side products generated in the reaction.
E. K. Baylis, C. D. Campbell and J. G. Dingwall, J. Chem. Soc. Perkin Trans. 1, 2845 (1984); G. M. Kosolapoff and L. Maier, "Organic Phosphonous Compounds, Wiley-Interscience, N.Y. 1972, Vol. 4, pp. 288 and 294-295 and Vol. 7, page 11; R. N. Mehrotra, Can. J. Chem., 63, 663 (1985); and C. F. Guichard, Chem. Ber., 32 1572 (1899) disclose the oxidation of phosphonous acids or its esters to phosphonic acids or its esters which often requires strong, poisonous, expensive and gaseous reagents.
U.S. Pat. No. 4,452,790 to Karanewsky et al discloses phosphonyl hydroxyacyl amino acid derivatives having the structure ##STR10## wherein R.sub.1 includes lower alkyl, aminoalkyl, haloalkyl, aryl, arylalkyl, cycloalkyl and cycloalkylalkyl;
R.sub.2 includes H, lower alkyl, aminoalkyl, aryl, arylalkyl, cycloalkyl and cycloalkylalkyl; PA0 R.sub.3 includes H, lower alkyl and arylalkyl; and PA0 X is ##STR11## wherein R.sub.4 includes H, lower alkyl, halogen, keto, OH, amino, aryl, arylalkyl, lower alkoxy or arylalkyloxy; and R.sub.6 includes H, lower alkyl, arylalkyl, alkali metal salt such as Li, Na or K, benzhydryl or ##STR12## wherein R.sub.15 is H, lower cycloalkyl or phenyl, and R.sub.16 is H, lower alkyl, lower alkoxy, phenyl, or R.sub.15 and R.sub.16 taken together are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --CH.dbd.CH-- or ##STR13## PA0 R.sub.2 is H, lower alkyl, aminoalkyl, aryl, aralkyl, cycloalkyl or cycloalkylalkyl; PA0 R.sub.2' is H or lower alkyl; PA0 R.sub.3 is H, lower alkyl or aralkyl; PA0 R.sub.4 includes H, lower alkyl, halogen, keto, OH, amino, aryl, arylalkyl, lower alkoxy or arylalkyloxy; and PA0 R.sub.6 includes H, lower alkyl, arylalkyl, alkali metal salt such as Li, Na or K, benzhydryl or ##STR21## wherein R.sub.15 is H, lower alkyl, cycloalkyl or phenyl, and R.sub.16 is H, lower alkyl, lower alkoxy, phenyl, or R.sub.15 and R.sub.16 taken together are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --CH.dbd.CH-- or ##STR22##
In the above patent, Karanewsky et al teach that the above compounds may be prepared treating a phosphonic acid ##STR14## with a chlorinating agent such as phosphorus pentachloride to form the dichloride ##STR15## which is reacted with an alcohol ##STR16## in the presence of triethylamine, followed by an alcohol EQU R.sub.3 OH
to form ##STR17## which is hydrolyzed by treatment with strong base to form the corresponding acid ##STR18##
The above acid or its activated form is then coupled with an imino or amino acid H--X.
In the above reaction, if R.sub.1 is p-hydroxyphenylalkyl, di-hydroxyphenylalkyl, aminoalkyl, guanidinyl, mercaptoalkyl or imidazolyl, then the hydroxyl, amino, imidazolyl, mercaptan or guanidinyl function should be protected during the coupling reaction. Similarly, if R.sub.2 is aminoalkyl, then the amino group should be similarly protected.